Abstract
Cyclopentenone prostaglandins (PGs) have antiproliferative activity on various tumor cell growth in vitro. Particularly, 9-deoxy-delta(9,12)-13,14-dihydro PGD(2) (delta(12)-PGJ(2)) was reported for its antineoplastic and apoptotic effects on various cancer cells, but its mechanism inducing apoptosis is still not clear. In this study, we have characterized apoptosis induced by delta(12)-PGJ(2) in HeLa cells. Treatment of delta(12)-PGJ(2) induced apoptosis as indicated by DNA fragmentation, chromatin condensation, and formation of apoptotic body. We also observed release of cytochrome c from mitochondria and activation of caspase cascade including caspase-3, -8, and -9. And the pan-caspase inhibitor z-Val-Ala-Asp (OMe) fluoromethyl-ketone (z-VAD-fmk) and Q-Val-Asp (OMe)-CH(2)-OPH (Q-VD (OMe)-OPH) prevented cell death induced by delta(12)-PGJ(2) showing participation of caspases in this process. However, protein expression level of Bcl-2 family was not altered by delta(12)-PGJ(2), seems to have no effect on HeLa cell apoptosis. And ZB4, an antagonistic Fas-antibody, exerted no effect on the activation of caspase 8 indicating that Fas receptor-ligand interaction was not involved in this pathway. Treatment of delta(12)-PGJ(2) also leads to suppression of nuclear factor kappaB (NF-kappaB) as indicated by nuclear translocation of p65/RelA and c-Rel and its DNA binding ability analyzed by EMSA. Taken together, our results suggest that delta(12)-PGJ(2)-induced apoptosis in HeLa cell utilized caspase cascade without Fas receptor-ligand interaction and accompanied with NF-kappaB inactivation.
Highlights
Apoptosis is an evolutionary conserved process that removes damaged or unwanted cells
Our results suggest that ∆12-P G J2-induced apoptosis in H eLa cell utilized caspase cascade without Fas receptor-ligand interaction and accom panied with N F-κB in ac tiva tio n
Apoptosis is induced by a wide variety of cellular stresses such as DNA damage, UV radiation, ionizing radiation and oxidative stress (Nagata, 1997)
Summary
Apoptosis is an evolutionary conserved process that removes damaged or unwanted cells. The expression of genes and their products, including p53, c-myc, heat shock protein 70, Sox-4 (Sry-HMG box gene) and SSF-1 (a novel splicing factor), are up- and down-regulated by presence of ∆12-PGJ2 in human hepatocarcinoma cells. These genes and their products serve as a positive or negative regulator in ∆12-PGJ2-induced apoptotic pathway in tumor cells (Lee et al, 1995; Ahn et al, 1998; Ahn et al, 1999; Ahn et al, 2002). We have evaluated possible apoptotic mechanism(s) of ∆12-PGJ2 in human cervical cancer HeLa cells by determining alteration of apoptosisrelated molecules including bcl-2, bax, caspase 9, caspase 8, caspase 3, cytochrome C and NF-κB
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